Project Summary What we eat may be the single most important determinant of our health. Yet, science-based dietary recommendations remain, at best, generic and imperfect. One fundamental obstacle to more specific, tailored, and reliable dietary guidance is our lack of understanding of what happens to food in our body. Underlying the simple overall chemical reaction from dietary carbons to CO2 is diverse energy metabolism in individual tissues. Tissues take their fuels from the bloodstream, which carries not only nutrients directly from digestion but also metabolic intermediates released by tissues themselves. How do these circulatory nutrients contribute to tissues as fuels? And by which tissues is each of the circulatory nutrients produced? In this proposal, I propose to use in vivo isotopic tracing and quantitative modeling to systematically determine the tissue sinks and sources of circulatory nutrients in mammals. In Aim 1, I will focus on tissues and quantify their fuel usage from circulatory nutrients by tracing isotopic labeled nutrients into their TCA cycle. In Aim 2, I will focus on important circulatory nutrients and quantify their tissue sources and sinks by an innovative approach of combining isotopic tracer infusion and arteriovenous labeling difference measurements. Upon successful completion of my proposed research, we will move closer to a holistic and quantitative understanding of the energy metabolism in mammals. The work will lay the foundation for eventual improved understanding of the relationship between diet and health. This proposal will also allow me to successfully transition to an independent investigator.